1. Field of the Invention
The present invention relates to a novel and improved process for preparing 4-acyloxy-2-azetidinone derivatives which is an intermediate useful for synthesis of penem or carbapenem antibiotics. More specifically, the present invention relates to a novel process for preparing 4-acyloxy-2-azetidinone derivatives having the following formula (I): ##STR3## or their optical isomers, in which
R.sub.1 represents a hydroxy-protecting group; and
R.sub.3 represents an acyl group.
2. Background Art
3-[1'-(R)-hydroxyethyl]-4-acyloxy-2-azetidinone, and its derivatives in which hydroxy group or .beta.-lactam amino group is protected with various protecting groups have been used as an intermediate for synthesis of penem compounds or carbapenem compounds, and the methods for their preparation have been disclosed in numerous publications. Typical examples of the known methods are a method for preparing 4-acetoxy-2-azetidinone derivatives from 4-acetyl-2-azetidinone derivatives by means of Baeyer-Villiger oxidation [see, Tetrahedron Lett., 5205 (1981); 5631 (1989)]; a method for preparing 4-acetoxy-2-azetidinone derivatives from 4-hydroxycarbonyl-2-azetidinone derivatives using Pb(OAc)4 [see, Tetrahedron Lett., 2923 (1982)]; a method for preparing 4-acetoxy-2-azetidinone from.4-trialkylsilyloxy-2-azetidinone derivatives [see, Japanese Laid-open Patent Publication No. 84057/87; European Patent No. 167155]; a method for preparing 4-acetoxy-2-azetidinone derivatives from 2-azetidinone derivatives having no substituent on C-4 position [see, European Patent No. 488611; J. Am. Chem. Soc., 7820 (1990)], and the like.
In addition, some methods for preparing 3-[1'-(R)-hydroxyethyl]-4-arylthio-2-azetidinone derivatives, for example, a method for preparing 4-arylthio-2-azetidinone derivatives by condensation reaction of isocyanate derivatives and vinyl sulfide derivatives [see, Japanese Laid-open Patent Publication No. 97260/86], a method for preparing 3-(1-hydroxyethyl)-4-arylthio-2-azetidinone derivatives by introducing 1-hydroxyethyl group into C-3 position of 4-arylthio-2-azetidinone derivatives in which C-3 position remains unsubstituted [see, Japanese Laid-open Patent Publication No. 44355/84] and the like, have also been reported. Said arylthio derivatives are generally converted into the 4-acyloxy or 4-arylsulfone derivatives which are used for preparing 3-[1'-(R)-hydroxyethyl]-4-acyloxy-2-azetidinone derivatives. Particularly, the arylthio compounds have mainly converted into 4-acyloxy-2-azetidinone derivatives because of high reactivity of the compound having 4-acyloxy group.
Accordingly, the method for conversion of azetidinone derivatives having 4-arylthio group into 4-acyloxy compounds have been extensively studied. The presently known methods are a method using mercury salt [see, Chem. Pharm. Bull., 2899 (1981)] or copper salt [see, European Patent No. 372699].
However, the method using mercury salt could not be practically used in industrial scale because the use of a poisonous mercury salt as the reactant results in serious problems related to safety in operations and disposal of mercury-containing waste after the reaction. The method using copper salt has been proposed as an alternative method for such impractical method. However, although the copper salt is less poisonous than mercury salt, since copper itself is a heavy metal, the problem related to disposal of reaction waste could not be completely solved. Moreover, such heavy metal reactants are expensive and thus are not preferable in economical view.
Thus, the present inventors have extensively and intensively studied to develop a method which can convert 4-arylthio azetidinone compounds into 4-acyloxy azetidinone derivatives with a certain reactant, which is economical and can be safely handled, rather than heavy metal reactants used in the prior methods. As a result, we have identified that 3-[1'-(R)-hydroxyethyl]-4-arylthio-2-azetidinone can be economically and safely converted into 3-[1'-(R)-hydroxyethyl]-4-acyloxy-2-azetidinone by means of an organic compound, N-haloacylimide, as the reactant, which does not cause any problem related to toxicity and waste disposal. Thus, now we have completed the present invention.
Therefore, it is an object of the present invention to provide a novel process for preparing 4-acyloxy-2-azetidinone derivatives of formula (I), as defined above, using a N-haloacylimide reactant.
It is a further object of the present invention to provide a novel and improved process for preparing 4-acyloxy-2-azetidinone derivatives of formula (I), as defined above, or their optical isomers by reacting an 2-azetidinone derivative of formula (II), as defined below, with a N-haloacylimide in the presence of an organic carboxylic acid or a salt of an organic carboxylic acid.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Other many beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention, in addition to the scope of the invention defined by the claims.